EP1916522A1 - Säule mit getrennten Abschnitten stationärer Phase - Google Patents

Säule mit getrennten Abschnitten stationärer Phase Download PDF

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Publication number
EP1916522A1
EP1916522A1 EP06122913A EP06122913A EP1916522A1 EP 1916522 A1 EP1916522 A1 EP 1916522A1 EP 06122913 A EP06122913 A EP 06122913A EP 06122913 A EP06122913 A EP 06122913A EP 1916522 A1 EP1916522 A1 EP 1916522A1
Authority
EP
European Patent Office
Prior art keywords
separator
housing
stationary phase
particles
force
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06122913A
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English (en)
French (fr)
Inventor
Klaus Witt
Bernd-Walter Hoffmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Agilent Technologies Inc
Original Assignee
Agilent Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Agilent Technologies Inc filed Critical Agilent Technologies Inc
Priority to EP06122913A priority Critical patent/EP1916522A1/de
Priority to US11/906,693 priority patent/US20080099402A1/en
Publication of EP1916522A1 publication Critical patent/EP1916522A1/de
Withdrawn legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6052—Construction of the column body
    • G01N30/6069—Construction of the column body with compartments or bed substructure
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6052—Construction of the column body
    • G01N30/606—Construction of the column body with fluid access or exit ports
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6052—Construction of the column body
    • G01N30/6065—Construction of the column body with varying cross section
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/60—Construction of the column
    • G01N30/6095—Micromachined or nanomachined, e.g. micro- or nanosize

Definitions

  • the present invention relates to column devices for separating different compounds of a mobile phase.
  • HPLC high performance liquid chromatography
  • a mobile phase usually an analyte which may comprise a sample fluid to be analyzed
  • a column comprising - as a stationary phase - a material capable of separating different compounds that are dissolved in the mobile phase.
  • material e.g. so called beads which may comprise silica gel
  • HPLC column may be coupled or connected to other elements (like a control unit, a pump, containers including samples to be analyzed) by e.g. using fitting elements.
  • fitting elements may contain porous parts such as screens or frit elements.
  • a flow of the mobile phase traverses the column filled with the stationary phase, and due to the physical interaction between the mobile and the stationary phase a separation of different compounds or components may be achieved.
  • the separation characteristics is usually adapted in order to separate compounds of such sample fluid.
  • the term compound, as used herein, shall cover compounds which might comprise one or more different components.
  • the stationary phase is subject to a mechanical force generated in particular by a hydraulic pump that pumps the mobile phase usually from an upstream connection of the column to a downstream connection of the column. As a result of flow, depending on the physical properties of the stationary phase and the mobile phase, a relatively high pressure occurs across the column.
  • US 5,908,552 A and US 5,858,241 A both disclose columns for capillary chromatographic separations. Other columns are disclosed e.g. in US 5,651,886 , US 5,071,610 and US 5,338,448 , WO 2006/000469 or by the unpublished patent applications WO/ EP2006/060645 and EP 05110782.9 , both by the same applicant Agilent Technologies.
  • the column or column device has a stationary phase comprising a plurality of particles.
  • the particles may interact with the mobile phase in order to separate different compounds, dissolved in the mobile phase.
  • a housing is provided for at least partly housing the stationary phase.
  • Such housing may be a tube, several tubes, or other components or devices (in any suitable shape) combined allowing to receive, contain and retain the stationary phase, but also to withhold the pressure requirements resulting from driving the mobile phase through the column. With smaller sizes of the stationary phase particles, pressures of about 1000 bar and above might be used in order to gain analysis speed and resolution.
  • the stationary phase is separated into two or more sections of stationary phase(s), whereby a separator is provided between two neighboring sections of stationary phase.
  • Each separator is force-coupling with the housing, or in case the stationary phase is housed by plural individual housing elements, each separator is force-coupled to or with at least one of such housing elements.
  • Such separator (or each separator in case of plural separators) allows that a force - in this case e.g. a mechanical force -, which may result from the mobile phase passing through a section of the stationary phase which is located upstream neighboring to the separator, can be at least partly transmitted by means of the separator to the housing (or housing element) to which the separator is force-coupled.
  • force from the stationary phase section neighboring upstream to the separator is at least reduced (and ideally even eliminated), and correspondingly at least partly reduced before subjected onto the stationary phase section neighboring downstream to the separator.
  • a force exerting on a particle of the stationary phase abutting from upstream onto the separator is at least partly transmitted through the separator and thus exerted onto the housing, so that only a reduced force - or in best case no force - from this (upstream) particle is subjected on a particle located downstream from the separator.
  • a force between neighboring abutting particles is directly exerted from the upstream particle to the downstream particles, thereby distributed and accumulating in the direction of flow of the mobile phase.
  • the force as "seen" by each particle of the stationary phase results from the rate of flow of the mobile phase passing this particle as well as from particles abutting from upstream.
  • the force in downstream direction is accumulated with each particle abutting further downstream.
  • the separator located between two such particles in downstream direction virtually “interrupts” such chain of force accumulation, so that only a limited force is exerted on the downstream particle, and ideally the force is fully transmitted and exerted onto the housing.
  • the effect and result from excessive application of force onto particles of the stationary phase may damage the particles or at least a certain percentage of particles.
  • Elastic particles might collapse entirely or in parts.
  • Brittle particles might break and crumble into fines and particle fragments.
  • occurring fines may pass such parts and may be flushed out of the column.
  • occurring fragments may cause the packed bed to be reestablished into a suboptimal non-uniform particle bed structure.
  • the structure of the packed bed may be impaired.
  • the volume of the stationary phase may be reduced, e.g. creating channels within the column packing or creating a void volume in particular at an inlet side (upstream) of the column device.
  • Void volumes are generally undesirable and might lead to increased dispersion of the compounds to be separated, thus decreasing the resolution of the separation process.
  • smaller sized particles may partially stick between other pores, inside a filter or frit pores at the outlet of the column (leading to an increase in the pressure drop across the column), or that such smaller size particles can pass through the outlet of the column, eventually disturbing downstream devices or processes.
  • the stationary phase is located between an inlet and outlet of the column device.
  • a filter may be provided adapted for preventing the particles from passing through the filter.
  • Such filter is preferably located at the outlet of the column but might also be located at the inlet or at both sides.
  • Such filter might be or comprise porous parts such as screens or frit elements, a frit, or any other suitable device or element as known in the art and in particular as disclosed by the documents cited in the introductory part.
  • Such filter might have a pore structure allowing fluids to pass through, usually with a maximum pore size smaller than the column particles, so that the column particles remain retained inside the column.
  • the separator might even be embodied in the same way as the filter, e.g. a frit, thus allowing using the same parts in multiple places.
  • the stationary phase is divided by the one or more separators into different sections.
  • Each section comprises a plurality of particles which may be individual particles and/or particles bound together, e.g. as known in the art such as by temperature treatment, chemical reaction, gluing, etc.
  • the particles are preferably packed together by application of pressure and/or force.
  • At least one section of the stationary phase comprises particles which are different from particles in another section.
  • different separation characteristics can be achieved along the separation path of the column.
  • the separator is at least partly permeable for the mobile phase, thus allowing the mobile phase to pass through the column.
  • the separator might be embodied from particles of the stationary phase, it might also or in addition comprise separate elements such as a filter, a frit, a screen, a membrane, a combination of the above or any other element as known in the art.
  • force-coupling i.e. by applying adequate pressure during the manufacturing process of the column device, such as using an appropriate liquid with or without ultrasonic support, a mixture of different liquids, a supercritical fluid
  • a chemical reaction e.g.
  • temperature processing such as heating as disclosed in the aforementioned US 5,858,241 , gluing (e.g. as disclosed in the afore mentioned unpublished EP05110782.9 ), or any other suitable process might be used.
  • the separator is provided to be at least partly elastically deformable (e.g. on application of force). This might result from the physical characteristic of the separator and/or the specific applied way of coupling the separator to the housing.
  • the separator might be bendable in flow direction as result from an application of force.
  • the separator might be embodied elastically deformable as disclosed in the aforementioned unpublished WO/ EP2006/060645 .
  • an inner surface of the housing facing the stationary phase, the separator, or both is provided with an area of a defined surface roughness. This can support or achieve the force coupling between the separator and the housing.
  • the force coupling between the separator and the housing might be achieved by form fitting and/or force fitting.
  • the housing comprises a section of reduced or increased diameter, so that the separator is kept in position by form fitting.
  • the separator can be provided by an element separate/different from the housing, the separator might also be formed as an integral part of the housing. E.g. in case of an application in a micro-fluidic device, one or more separators might be provided as integral parts of the general walls. In one embodiment, wherein the column comprises one separator, the column is packed sequentially from both directions.
  • the particles of the stationary phase might be embodied as porous and/or non-porous particles, as well known in the art.
  • Typical materials suitable for the stationary phase can be inorganic metal- or non metal oxides such as pure Silica or any chemical modifications of Silica, oxides of Zirconia, Titania, Alumina, graphitized carbon or organic polymers such as Polystyrene, polyvinyl alcohols, metacrylates or any other derivatives.
  • Embodiments of the invention have also been shown advantageous when going to smaller sizes of the particles.
  • the individual interstitial volumes between discrete particles is lower, which increases the linear velocity of the flow around the particles, resulting in higher pressure drop across unit length of the column. Accordingly, the number of particles per volume increases with lower particle sizes.
  • the system pressure is increased.
  • porous particles of smaller size a relatively lower amount of the mobile phase passes along outside each particle. As a result the percentage of liquid flowing through a porous particle increases, increasing the force acting on that particle, which again leads to more force per unit length of the separation column being accumulated.
  • the column device is preferably applied in the so-called high performance liquid chromatography (HPLC) with pressure ranges of (currently) a few bar and up to 1000 bar (and even beyond) being exerted on the column in order to move the samples to be separated and measured with support of the mobile phase through the separation device.
  • HPLC high performance liquid chromatography
  • the invention has been shown in particular useful with high speed applications. These applications use high flow rates of the mobile phase to dramatically reduce the separation time and very small particles to create more separation efficiency. Both dramatically increase the overall pressure drop across the column, often close to the system's pressure specification limits.
  • Embodiments of the column device can be used in a separation device or system which might comprise further units such as one or more pumps for driving the mobile phase, one or more sampling units for introducing sample(s) into the mobile phase, one or more thermostats for temperature control, one or more detectors for detecting separated compounds, and one or more fractionating units for the collection of separated compounds.
  • a separation device or system which might comprise further units such as one or more pumps for driving the mobile phase, one or more sampling units for introducing sample(s) into the mobile phase, one or more thermostats for temperature control, one or more detectors for detecting separated compounds, and one or more fractionating units for the collection of separated compounds.
  • Such separation system might also or in addition comprise any other unit as known in the art and in particular such as disclosed in the aforementioned prior art documents.
  • the column device comprises a plurality of inner tubes.
  • Each inner tube is housing a section of the stationary phase.
  • a separator is provided between two inner tubes.
  • the inner housing together with the one or more separators are then housed by the housing.
  • the one or more separators might be force coupled either directly with the housing or by means of the inner tubes, with at least one of the inner housing being force-coupled with the housing.
  • the inner housings as well as the housing are embodied as tubes.
  • the inner housings are placed into the housing tube, with two neighboring inner housing tubes locating one separator.
  • Figure 1 shows an example of a separation system 10 for separating compounds dissolved in a mobile phase 20.
  • Figure 2A shows a typical embodiment of a column 50.
  • Figure 2B illustrates the occurrence of a force onto the particles 110.
  • Figure 3 illustrates the effect resulting from the introduction of the separator 200.
  • FIGS 4A-4C and Figures 5A-5B show embodiments of the separator 200.
  • Figure 6 shows an embodiment of the column 50 provided as a microfluidic application.
  • the separation system 10 might comprise a driving unit 30 for driving the mobile phase 20.
  • driving unit 30 can be a pump such as disclosed in EP 0309596 A or any other suitable HPLC pump as known in the art.
  • a sampling unit 40 might be provided for introducing a sample to be analyzed into the mobile phase 20.
  • a column 50 is located downstream to the driving unit 30 and the sampling unit 40. The column device 50 is adapted for separating different compounds of the sample as introduced by the sampling unit 40. The column 50 will be described in greater detail below.
  • a detector 60 can be coupled downstream to the column 50 in order to detect the separated compounds. Such detection might be optically, electrically or by any other means as known in the art. Typical types of detection devices as applied in HPLC are UV- or UV/Visible absorbance detection devices, Fluorescence or Light scattering detection devices, Refractive index detectors or any other light transmission/emission based detectors, conductivity or electro-chemical detectors, or chemical mass based detection devices, such as a mass spectrometer and/or a combination of these detection devices.
  • a fractionating unit 70 can be provided for collecting separated analytes of injected sample(s) to be analyzed.
  • the separation system 10 can be embodied as a whole by or in parts by using components of the Agilent 1100 Series or the Agilent 1200 Series as provided by the applicant Agilent Technologies and disclosed under www.agilent.com .
  • Figure 2A shows a typical embodiment of a column 50 having a stationary phase 100 with a plurality of particles 110.
  • the column 50 further comprises an inlet 120 for receiving the mobile phase 20 and an outlet 130 for outletting the mobile phase, which shall be denoted as 20'.
  • a filter 140 is usually provided at the outlet 130 in order to retain the particles 110 from leaving the column 50.
  • the same or another filter 150 might be provided at the inlet 120, again for retaining the particles 110 within the column 50.
  • the stationary phase 100 is housed in a housing 160, which might be provided by one or more pieces.
  • Figure 2B illustrates the occurrence of a (mechanical) force onto the particles 110 as a result of the resistance of the stationary phase and the viscosity of the mobile phase 20 flowing through the column 50.
  • a first particle P1 experiences a force F1 from the flow of the mobile phase 20.
  • a particle P2, which is located further downstream of the mobile phase 20 and to which the particle P1 abuts to, is also subjected to a force F2 resulting from the flow of the mobile phase 20 but is also subjected to the force F1 from the particle P1 abutting to the particle P2.
  • Each further particle Pi located further downstream is subjected not only to the force Fi from the flow of the mobile phase 20, but also to the accumulated force from the particles located further upstream and abutting to each other.
  • any separation device 50 the particles are usually packed as closely together as possible to perform a high separation HPLC column.
  • the force F or Fi onto any particle will be greater than zero, even, if the force might be reduced in case of a deformation of any of the particles 110, in particular in case of plastic deformation.
  • the particle Pi can be permanently deformed or even damaged.
  • the particle can collapse (e.g. in case of elastic particles) or break into sub-particles e.g. in case of more brittle particles. This can lead e.g. to bed channeling and/or a void volume in particular in the region of the inlet 120, which then will cause a peak dispersion (of chromatographic peaks) and chromatographic band-spreading that reduces the resolution between two neighbored analytes when passing detector 60.
  • the smaller sized sub-particles might pass through, or plug, block or clog the filter 140, at least partly, which again can lead to a higher pressure drop across the column 50, and finally might reduce the separation performance of column 50.
  • Figure 3 illustrates the effect resulting from the introduction of the separator 200, which is force coupled with the housing 160.
  • Particle Pi which abuts from upstream to the separator 200 exerts the accumulated force Fi onto the separator 200 (rather than onto a neighboring particle as illustrated in Figure 2B).
  • a portion Fih of the force Fi is transmitted to the housing 160 and "absorbed" by the housing 160, and only a remaining portion Fi' is exerted from the separator 200 onto a particle P1 abutting downstream to the separator 200.
  • the separator 200 reduces the amount of the accumulated force Fi from particles located upstream and ideally eliminates such accumulated force.
  • Figure 4A shows an embodiment of the separator 200 being formed e.g. in-situ from particles 110.
  • the particles 110 are force-coupled together and also force-coupled with the housing 160, thus providing the separator 200.
  • the particles 110 might be coupled together and/or to the housing 160 by providing a chemical reaction between the inner surface of the housing 160 and the beads or a mixture of the beads with a second component.
  • a typical example might be a modified sol gel process as known in the art (see e.g.
  • Figure 4B shows another embodiment, wherein the separator 200 is provided by particles 110, e.g. as illustrated with respect to Figure 4A.
  • the force coupling between the separator 200 and the housing 160 is provided by a variation in the diameter of the housing 160, which might be embodied as a tube.
  • the diameter of the housing 160 is increased in the region of the location of the separator 200.
  • the diameter in the region downstream of the separator can be reduced. In either way the separator 200 is detained from moving in downstream direction.
  • Figure 4C shows another embodiment.
  • the separator 200 has been introduced into the housing 160, e.g. during an assembly or packaging process of the column.
  • the force coupling of the separator 200 with the housing 160 can be increased by exerting a force onto the region of the housing 160 where the separator 200 is located.
  • Adequate tools and methods as well-known in the art can be applied in order to reduce the inner diameter of the housing 160 in the region where the separator 200 abuts.
  • the diameter of the tube at least in a region of the location of the separator 200 is tapered (e.g. cone shaped) in downstream direction, so that the separator 200 is also form-fitted with the housing 160 in a similar way as shown with respect to Figure 4B.
  • FIG. 5A shows an embodiment wherein the housing 160 provides regions of smaller diameters in the direction of the downstream flow.
  • the housing 160 has a section 160A and a section 160B (located downstream with respect to section 160A).
  • a first separator 200A abuts to a transition area 300A between the housing sections 160A and 160B.
  • a second separator 200B abuts to a transition area 300B between the housing section 160B, and a further section 160C with lower diameter is located further downstream (with respect to the directional flow of the mobile phase 20).
  • the differences between the diameters of the housing sections 160A, 160B, 160C are preferably kept as small as possible in order to limit flow disturbance..
  • the separator 200 is form-fitted between two housing sections 160A and 160B.
  • the outer diameter of the separator 200 is larger than the inner diameter at least of the housing section 160B located downstream.
  • both housing sections 160A and 160B are embodied as tubes and separator 200 is embodied as a disc located between the housing sections 160A and 160B.
  • the housing sections 160A and 160B together with the separator 200 might be introduced into an outer tube 500, which might also be force coupled with the separator 200.
  • Figure 6 shows an embodiment of the column 50 provided as a microfluidic application.
  • the particles 110 are introduced into a channel 600.
  • the column 50 comprises four sections 100A, 100B, 100C and 100D of the stationary phase 100.
  • the separators 200 are provided by the same material as wherein the channel 600 has been formed into. Such material might be metal, silicon, glass, ceramic, plastic, or any other material suitable for micro-structuring techniques as known in the art.
  • Separator 200A is provided by leaving a small opening between two or more "bars" extending from a wall 610 of the channel substantially in a direction perpendicular to the direction of flow.
  • Separator 200B is provided by two or more bars with overlapping lengths but located closely together, so that a small opening between the parallel but overlapping bars is provided.
  • Separator 200C is similar as separator 200A but provides a plurality of small openings with two opening shown in Figure 6.
  • the separators 200 are preferably provided as retaining elements in order to retain the particles 110 from moving through the separator 200 in downstream direction.
  • Examples of embodiments of the separator 200 can be frit elements (as well-known in the art of column design), filter elements, or just a step in the surface reducing the channel height to smaller than or close to the particle size.

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EP06122913A 2006-10-25 2006-10-25 Säule mit getrennten Abschnitten stationärer Phase Withdrawn EP1916522A1 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP06122913A EP1916522A1 (de) 2006-10-25 2006-10-25 Säule mit getrennten Abschnitten stationärer Phase
US11/906,693 US20080099402A1 (en) 2006-10-25 2007-10-03 Column having separated sections of stationary phase

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Application Number Priority Date Filing Date Title
EP06122913A EP1916522A1 (de) 2006-10-25 2006-10-25 Säule mit getrennten Abschnitten stationärer Phase

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Cited By (5)

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WO2011012296A1 (en) 2009-07-30 2011-02-03 F. Hoffmann-La Roche Ag Moveable chromatography column separator
DE102011080527A1 (de) 2011-08-05 2013-02-07 Robert Bosch Gmbh Lateral durchströmtes Chromatographieelement
EP3047266A4 (de) * 2013-09-18 2017-04-12 Agilent Technologies, Inc. Flüssigkeitschromatografiesäulen mit strukturierten wänden
CN109475836A (zh) * 2016-07-04 2019-03-15 制药流体股份有限公司 化学反应器的生产
US11241638B2 (en) 2011-02-02 2022-02-08 Hoffmann-La Roche Inc. Chromatography column support

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US20130206667A1 (en) * 2010-11-16 2013-08-15 Nobull Innovation Llc Apparatus for making a chromatography column
US20130276519A1 (en) * 2012-04-20 2013-10-24 Dmitry V. Uborsky Methods of Separating Compounds
WO2014028211A1 (en) 2012-08-16 2014-02-20 Exxonmobil Chemical Patents Inc. Long chain branched epdm compositions and processes for production thereof

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Cited By (12)

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Publication number Priority date Publication date Assignee Title
WO2011012296A1 (en) 2009-07-30 2011-02-03 F. Hoffmann-La Roche Ag Moveable chromatography column separator
KR101477871B1 (ko) * 2009-07-30 2014-12-30 에프. 호프만-라 로슈 아게 이동식 크로마토그래피 컬럼 세퍼레이터
US9289699B2 (en) 2009-07-30 2016-03-22 Hoffmann-La Roche Inc. Moveable chromatography column separator
US10052567B2 (en) 2009-07-30 2018-08-21 Hoffmann-La Roche Inc. Moveable chromatography column separator
US11241638B2 (en) 2011-02-02 2022-02-08 Hoffmann-La Roche Inc. Chromatography column support
DE102011080527A1 (de) 2011-08-05 2013-02-07 Robert Bosch Gmbh Lateral durchströmtes Chromatographieelement
EP3047266A4 (de) * 2013-09-18 2017-04-12 Agilent Technologies, Inc. Flüssigkeitschromatografiesäulen mit strukturierten wänden
US10073068B2 (en) 2013-09-18 2018-09-11 Agilent Technologies, Inc. Liquid chromatography columns with structured walls
US10718743B2 (en) 2013-09-18 2020-07-21 Agilent Technologies, Inc. Liquid chromatography columns with structured walls
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